Pediatric HCV

More Than Two Roads in the Yellow Wood for the Pediatric HCV Patient

More than two roads

At The Liver Meeting 2013, held by the American Association for the Study of Liver Diseases in Washington, D.C., the atmosphere was almost euphoric, at least for speakers who were presenting the latest therapeutic triumphs over the hepatitis C virus.

Kathleen B. Schwarz, MD 

Kathleen B. Schwarz

The first trials of alpha interferon for adults with HCV genotype 1 in the 1990s showed a pathetic 8% to 10% sustained virologic response (27% for children). Thus, recent news that direct-acting antiviral (DAA) agents in combination with pegylated interferon and ribavirin had very high SVR in adults was just cause for celebration. Also of excitement was the news of FDA approval of sofosbuvir (Sovaldi, Gilead) and simeprevir (Olysio, Janssen Therapeutics) combined with other antivirals for patients aged 18 years and older — good news, at least for physicians treating adults who could afford the drugs. Even more exciting yet was the news that very high SVR rates could be achieved in adults treated with interferon-free regimens involving combinations of nucleoside analogues.

Questions remain, however, such as how to care for the approximately 46,000 US patients younger than 18 years with HCV infection and the estimated 50,000 newborns in the world who acquire HCV from their mothers each year (See Sidebar 1).

Sidebar 1.

Screening and Available Treatment Options

The American Academy of Pediatrics has recommended that newborns of mothers with HCV should be screened for anti-HCV when they reach age 18 months, because testing before that point could yield false-positive results.

The combination of pegylated interferon alpha-2b plus ribavirin is FDA approved for children aged 3 years and older; pegylated interferon alpha-2a plus ribavirin is FDA approved for children aged 5 years and older. Although these two drug combinations were well-tolerated enough in the studies to result in FDA approval for use in young patients, SVR rates for children with the most common profile of HCV genotype 1 with high viral load are only about 50% for either combination. In addition, pegylated interferon therapy in young patients is associated with influenza-like adverse effects, neutropenia and growth impairment.

So, when the physician encounters a new patient aged 3 years, it remains uncertain whether he should treat that child now or wait for newer therapies that are better tolerated and more effective.

Therapy is Under Rapid Flux

When considering these divergent roads for the pediatric HCV patient, one needs to reflect on the competing arguments that HCV in children is usually slowly progressive, but that some children may progress to cirrhosis over a few years. Some may even require liver transplantation or, more rarely, progress to hepatocellular carcinoma.

Although the new interferon-free regimens hold great promise, pediatric trials have yet to begin. There are two pediatric trials that are currently examining triple therapy — pegylated interferon/ribavirin plus telaprevir (Incivek, Vertex Pharmaceuticals) or boceprevir (Victrelis, Merck), which may produce SVR rates in the 70% range — but these studies are being conducted only in children with HCV genotype 1. Additionally, neither regimen is particularly well tolerated in this patient population.

The therapy of children with HCV is under rapid flux, yet there is a lack of published data with agents other than pegylated interferon plus ribavirin to guide treatment decisions. The recently published North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) Practice Guidelines: Diagnosis and Management of Hepatitis C Infection in Infants, Children and Adolescents could thus only provide advice about pegylated interferon plus ribavirin (See Sidebar 2).

Sidebar 2.

An Empiric Approach to Care

Given this rapid flux, health care professionals who care for children with HCV have had to take an empiric approach. The following is the approach that we use in our own practice:

  1. Treat the child who has at least a 70% chance of responding to pegylated interferon plus ribavirin; for example, the child with genotype 2 or 3 or genotype 1 with a low viral load (<600,000 IU/mL). It is thrilling for caregivers and physicians alike to be able to send such a child to kindergarten free of HCV. We do not believe that a liver biopsy is necessary for this group.
  2. For all other children, use the results of a liver biopsy to help guide treatment decisions. For children who have genotype 1 with aggressive inflammation and fibrosis, offer entry into one of the pediatric triple-therapy trials. For those with aggressive disease with non-genotype 1, offer therapy with pegylated interferon plus ribavirin.
  3. For the remainder with mild inflammation and fibrosis, waiting for interferon-free pediatric trials makes the most sense.

There are two exceptions to No. 3 for the children with mild disease, which involve caregivers who are highly motivated because of the timing of the life situation. One situation is the caregiver with a prekindergarten-age child who realizes it is much easier to get the treatment over and done with before school begins. The other situation is the caregiver with an adolescent who acquired HCV via injection drug use who has just been released from a treatment facility and may only be under the caregiver’s supervision for a couple of more years.

Promising Future

In conclusion, there are certainly more than two roads in the woods of treatment decisions regarding the child with HCV. Yet, we have come a long way from the day when only one-quarter of children with this infection responded.

We look forward to the day when promising new agents will lead the rest of HCV-infected children out of the woods for good.

References:
American Academy of Pediatrics. Hepatitis C. In: Pickering LK, ed. 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006:355-359.
Gonzalez-Peralta RP. J Pediatr Gastroenterol Nutr. 2009;48:630-635.
Jacobson K. J Pediatr Gastroenterol Nutr. 2002;34:52-58.
Jonas MM. Hepatology. 2012;56:523-531.
Mack CL. J Pediatr Gastroenterol Nutr. 2012;54:838-855.
Malik S. Pediatr Transplant. 2014;18:E64-E68.
Mohan P. Hepatology. 2013;58:1580-1586.
Roberts EA. Hepatology. 2002;36(5 Suppl 1):S106-113.
Schwarz KB. Gastroenterology. 2011;140:450-458.
Sulkowski MS. N Engl J Med. 2014;370:211-221.
Wirth S. Hepatology. 2005;41:1013-1018.
Zhu Y. World J Gastroenterol. 2013;19:8963-8973.
For more information:
Kathleen B. Schwarz, MD, is professor of pediatrics and director of the Pediatric Liver Center at Johns Hopkins Children’s Center. She was a co-author of the 2012 NASPGHAN Practice Guidelines: Diagnosis and Management of Hepatitis C Infection in Infants, Children and Adolescents. Schwarz can be reached at Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21287; email: kschwar3@jhmi.edu.
Disclosure: Schwarz reports no relevant financial disclosures.

More than two roads

At The Liver Meeting 2013, held by the American Association for the Study of Liver Diseases in Washington, D.C., the atmosphere was almost euphoric, at least for speakers who were presenting the latest therapeutic triumphs over the hepatitis C virus.

Kathleen B. Schwarz, MD 

Kathleen B. Schwarz

The first trials of alpha interferon for adults with HCV genotype 1 in the 1990s showed a pathetic 8% to 10% sustained virologic response (27% for children). Thus, recent news that direct-acting antiviral (DAA) agents in combination with pegylated interferon and ribavirin had very high SVR in adults was just cause for celebration. Also of excitement was the news of FDA approval of sofosbuvir (Sovaldi, Gilead) and simeprevir (Olysio, Janssen Therapeutics) combined with other antivirals for patients aged 18 years and older — good news, at least for physicians treating adults who could afford the drugs. Even more exciting yet was the news that very high SVR rates could be achieved in adults treated with interferon-free regimens involving combinations of nucleoside analogues.

Questions remain, however, such as how to care for the approximately 46,000 US patients younger than 18 years with HCV infection and the estimated 50,000 newborns in the world who acquire HCV from their mothers each year (See Sidebar 1).

Sidebar 1.

Screening and Available Treatment Options

The American Academy of Pediatrics has recommended that newborns of mothers with HCV should be screened for anti-HCV when they reach age 18 months, because testing before that point could yield false-positive results.

The combination of pegylated interferon alpha-2b plus ribavirin is FDA approved for children aged 3 years and older; pegylated interferon alpha-2a plus ribavirin is FDA approved for children aged 5 years and older. Although these two drug combinations were well-tolerated enough in the studies to result in FDA approval for use in young patients, SVR rates for children with the most common profile of HCV genotype 1 with high viral load are only about 50% for either combination. In addition, pegylated interferon therapy in young patients is associated with influenza-like adverse effects, neutropenia and growth impairment.

So, when the physician encounters a new patient aged 3 years, it remains uncertain whether he should treat that child now or wait for newer therapies that are better tolerated and more effective.

Therapy is Under Rapid Flux

When considering these divergent roads for the pediatric HCV patient, one needs to reflect on the competing arguments that HCV in children is usually slowly progressive, but that some children may progress to cirrhosis over a few years. Some may even require liver transplantation or, more rarely, progress to hepatocellular carcinoma.

Although the new interferon-free regimens hold great promise, pediatric trials have yet to begin. There are two pediatric trials that are currently examining triple therapy — pegylated interferon/ribavirin plus telaprevir (Incivek, Vertex Pharmaceuticals) or boceprevir (Victrelis, Merck), which may produce SVR rates in the 70% range — but these studies are being conducted only in children with HCV genotype 1. Additionally, neither regimen is particularly well tolerated in this patient population.

The therapy of children with HCV is under rapid flux, yet there is a lack of published data with agents other than pegylated interferon plus ribavirin to guide treatment decisions. The recently published North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) Practice Guidelines: Diagnosis and Management of Hepatitis C Infection in Infants, Children and Adolescents could thus only provide advice about pegylated interferon plus ribavirin (See Sidebar 2).

Sidebar 2.
PAGE BREAK

An Empiric Approach to Care

Given this rapid flux, health care professionals who care for children with HCV have had to take an empiric approach. The following is the approach that we use in our own practice:

  1. Treat the child who has at least a 70% chance of responding to pegylated interferon plus ribavirin; for example, the child with genotype 2 or 3 or genotype 1 with a low viral load (<600,000 IU/mL). It is thrilling for caregivers and physicians alike to be able to send such a child to kindergarten free of HCV. We do not believe that a liver biopsy is necessary for this group.
  2. For all other children, use the results of a liver biopsy to help guide treatment decisions. For children who have genotype 1 with aggressive inflammation and fibrosis, offer entry into one of the pediatric triple-therapy trials. For those with aggressive disease with non-genotype 1, offer therapy with pegylated interferon plus ribavirin.
  3. For the remainder with mild inflammation and fibrosis, waiting for interferon-free pediatric trials makes the most sense.

There are two exceptions to No. 3 for the children with mild disease, which involve caregivers who are highly motivated because of the timing of the life situation. One situation is the caregiver with a prekindergarten-age child who realizes it is much easier to get the treatment over and done with before school begins. The other situation is the caregiver with an adolescent who acquired HCV via injection drug use who has just been released from a treatment facility and may only be under the caregiver’s supervision for a couple of more years.

Promising Future

In conclusion, there are certainly more than two roads in the woods of treatment decisions regarding the child with HCV. Yet, we have come a long way from the day when only one-quarter of children with this infection responded.

We look forward to the day when promising new agents will lead the rest of HCV-infected children out of the woods for good.

References:
American Academy of Pediatrics. Hepatitis C. In: Pickering LK, ed. 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006:355-359.
Gonzalez-Peralta RP. J Pediatr Gastroenterol Nutr. 2009;48:630-635.
Jacobson K. J Pediatr Gastroenterol Nutr. 2002;34:52-58.
Jonas MM. Hepatology. 2012;56:523-531.
Mack CL. J Pediatr Gastroenterol Nutr. 2012;54:838-855.
Malik S. Pediatr Transplant. 2014;18:E64-E68.
Mohan P. Hepatology. 2013;58:1580-1586.
Roberts EA. Hepatology. 2002;36(5 Suppl 1):S106-113.
Schwarz KB. Gastroenterology. 2011;140:450-458.
Sulkowski MS. N Engl J Med. 2014;370:211-221.
Wirth S. Hepatology. 2005;41:1013-1018.
Zhu Y. World J Gastroenterol. 2013;19:8963-8973.
For more information:
Kathleen B. Schwarz, MD, is professor of pediatrics and director of the Pediatric Liver Center at Johns Hopkins Children’s Center. She was a co-author of the 2012 NASPGHAN Practice Guidelines: Diagnosis and Management of Hepatitis C Infection in Infants, Children and Adolescents. Schwarz can be reached at Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21287; email: kschwar3@jhmi.edu.
Disclosure: Schwarz reports no relevant financial disclosures.